JAK/STAT抑制剂在TNBS诱发大鼠结肠炎中的作用  

Role of the Janus kinase/signal transducer and activator of transcription pathway in the pathogenesis of trinitrobenzenesulfonic acidinduced experimental colitis in rats

作　　者：杨涓[1] 缪应雷[1] 

机构地区：[1]昆明医学院第一附属医院消化内科,云南省昆明市650032

出　　处：《世界华人消化杂志》2009年第25期2571-2576,共6页World Chinese Journal of Digestology

基　　金：云南省自然科学基金资助项目;No.2005C0069M~~

摘　　要：目的:探讨抑制Janus激酶/信号转导和转录激活子(JAK/STAT)通路在大鼠结肠炎发病机制中的作用.方法:建实验性大鼠结肠炎模型后,给予JAK特异性抑制剂AG490和STAT抑制剂雷帕霉素(RPM),腹腔注射治疗1wk后处死大鼠,观察结肠炎症改变并进行评分,采用蛋白印迹法(Western blot)检测MMP-1、MMP-2、MMP-3、TIMP-1蛋白表达;用明胶酶谱法检测结肠组织中MMP-2的活性.结果:与对照组相比,AG490治疗组肠道损伤积分降低(5.50±2.16分vs8.53±2.18分,P=0.012);RPM治疗组肠道损伤积分(5.17±1.80分)较对照组低(P<0.05).AG490组和RPM组MMP-1、MMP-2的蛋白质表达量均明显低于对照组(均P<0.05),而两实验组分别与对照组比较其MMP-3、TIMP-1蛋白质表达均无明显差异(均P>0.05).与对照组相比,两实验组MMP-2的活性均显著下降(P<0.05).结论:AG490和RPM通过阻断JAK/STAT信号通路的活化能缓解大鼠结肠炎,这一作用可能是通过抑制MMP-1、MMP-2的表达来实现的.AIM： To investigate the role of the Janus kinase/ signal transducer and activator of transcription （STAT） signaling pathway in the pathogenesis of trinitrobenzenesulfonic acid （TNBS）-induced experimental colitis in rats.METHODS： TNBS was used to induce experimental colitis in rats. The rats were then intraperitoneally injected with rapamycin （RPM） and AG490 （a specific inhibitor of Janus kinase）. Colonic inflammation was evaluated by histology. Western blot was used to detect the expression of matrix metalloproteinase （MMP）-I, MMP-2,MMP-3 and ITMP-1 proteins in the colon. Gelatin zymogTaphy was used to examine the activity of MMP-2 in colitis.RESULTS： The pathological inflammation scores in the AG490 treatment group and RPM treatment group were significantly lower than that in the control group （5.50±2.16 and 5.17±1.80 vs 8.53±2.18, respectively; P = 0.012 and P 〈 0.05）. The expression levels of MMP-1 and MMP-2 proteins in the AG490 treatment group and RPM treatment group were significantly lower than those in the control group （all P 〈 0.05）. In contrast, there were no significant changes in the expression levels of MMP-3 and TIMP-1 proteins between the control group and the two treatment groups （both P 〉 0.05）. Compared with the control group, the activity of MMP-2 was obviously reduced in the two treatment groups （both P 〈 0.05）.CONCLUSION： Inhibition of the JAK/STAT signaling pathway by AG490 or RPM reduces disease activity in TNBS-induced experimental colitis through downregulation of MMP-1 and MMP-2 mRNA expression in colonic tissue.

关 键 词：AG490 雷帕霉素 JAK/STAT信号转导通路 实验性结肠炎 基质金属蛋白酶 

分 类 号：R574.62[医药卫生—消化系统]